Systematic characterization of mutations altering protein degradation in human cancers

Tokheim, Collin; Wang, Xiaoqing; Timms, Richard T.; Zhang, Boning; Mena, Elijah L.; Wang, Binbin; Chen, Cynthia; Ge, Jun; Chu, Jun; Zhang, Wubing; Elledge, Stephen J.; Brown, Myles; Liu, X. Shirley

doi:10.1016/j.molcel.2021.01.020

Cited by 51 publications

(37 citation statements)

References 128 publications

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“…UCHL1 is an oncogene, and a recent study showed that high expression of UCHL1 is correlated with worse overall survival in melanoma patients 58 . UCHL1 was previously reported to be N-terminally ubiquitinated 44 , and the enzyme responsible for this modification was unknown.…”

Section: Discussionmentioning

confidence: 99%

Antibody toolkit reveals N-terminally ubiquitinated substrates of UBE2W

Davies¹,

Vidal

Phu³

et al. 2021

Nat Commun

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The ubiquitin conjugating enzyme UBE2W catalyzes non-canonical ubiquitination on the N-termini of proteins, although its substrate repertoire remains unclear. To identify endogenous N-terminally-ubiquitinated substrates, we discover four monoclonal antibodies that selectively recognize tryptic peptides with an N-terminal diglycine remnant, corresponding to sites of N-terminal ubiquitination. Importantly, these antibodies do not recognize isopeptide-linked diglycine (ubiquitin) modifications on lysine. We solve the structure of one such antibody bound to a Gly-Gly-Met peptide to reveal the molecular basis for its selective recognition. We use these antibodies in conjunction with mass spectrometry proteomics to map N-terminal ubiquitination sites on endogenous substrates of UBE2W. These substrates include UCHL1 and UCHL5, where N-terminal ubiquitination distinctly alters deubiquitinase (DUB) activity. This work describes an antibody toolkit for enrichment and global profiling of endogenous N-terminal ubiquitination sites, while revealing functionally relevant substrates of UBE2W.

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Section: Discussionmentioning

confidence: 99%

Antibody toolkit reveals N-terminally ubiquitinated substrates of UBE2W

Davies¹,

Vidal

Phu³

et al. 2021

Nat Commun

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“…UBA6 plays an important role in embryogenesis and multiple pathogeneses of diseases 27,28 , however, the impact of UBA6 on tumor-intrinsic immunogenicity has been never addressed before. Interestingly, a recent report indicates the important role of ubiquitin-proteasome system (UPS) dysregulation in human cancer and underscores the potential therapeutic utility of targeting the UPS 43 . Despite abnormal expressions in UBA6 are found in several types of carcinomas, the function of UBA6 in antitumor immunity and immunotherapy is unclear.…”

Section: Discussionmentioning

confidence: 99%

Inhibiting tumor cell-intrinsic UBA6 by inosine augments tumor immunogenicity

Zhang

Jiang

et al. 2021

Preprint

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Metabolic alteration influences cancer immunity. However, the role and mechanism of metabolic adaption on immune checkpoint blockade (ICB) responses remains ill-defined. Here, to identify metabolites that modulate ICB sensitivity, metabolomic profiling in mouse tumor models and cancer patients treated with ICB was performed. We identified that metabolite inosine was associated with ICB sensitivity in mice and humans, and overcame ICB resistance in several mouse tumor models. Notably, inosine sensitized tumor cells to T cell-mediated cytotoxicity by amplifying tumor-intrinsic immunogenicity. Chemical proteomics further identified that inosine directly bound and inhibited ubiquitin-activating enzyme UBA6. Tumor UBA6 loss augmented tumor immunogenicity and substituted the synergistic effect of inosine in combination with ICB. Clinically, tumor UBA6 expression negatively correlated with ICB response in cancer patients. Thus, we reveal an unappreciated function of inosine on tumor-intrinsic immunogenicity and provide UBA6 as a candidate target for immunotherapy.

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“…A detailed analysis of degrons in cancers is discussed in [ 7 ] and the reader is referred to a detailed description of degrons therein (Table 1 in [ 7 ]). Beyond specific examples, leveraging machine learning and using cancer datasets, Takheim et al found that mutations affecting degrons play an important role in driving tumorigenesis [ 41 ]. The authors developed “deepDegron”, a machine learning method that predicts the impact of mutations or degron loss on protein stability, and validated these predictions for mutations in the degrons of GATA3 and PPM1D that result in stable proteins.…”

Section: Evading Recognition I: Protein Stabilization Due To Lacking or Mutated Degradation Signalsmentioning

confidence: 99%

From the Evasion of Degradation to Ubiquitin-Dependent Protein Stabilization

Ahmad

Oknin-Vaisman

Bitman-Lotan

et al. 2021

Cells

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A hallmark of cancer is dysregulated protein turnover (proteostasis), which involves pathologic ubiquitin-dependent degradation of tumor suppressor proteins, as well as increased oncoprotein stabilization. The latter is due, in part, to mutation within sequences, termed degrons, which are required for oncoprotein recognition by the substrate-recognition enzyme, E3 ubiquitin ligase. Stabilization may also result from the inactivation of the enzymatic machinery that mediates the degradation of oncoproteins. Importantly, inactivation in cancer of E3 enzymes that regulates the physiological degradation of oncoproteins, results in tumor cells that accumulate multiple active oncoproteins with prolonged half-lives, leading to the development of “degradation-resistant” cancer cells. In addition, specific sequences may enable ubiquitinated proteins to evade degradation at the 26S proteasome. While the ubiquitin-proteasome pathway was originally discovered as central for protein degradation, in cancer cells a ubiquitin-dependent protein stabilization pathway actively translates transient mitogenic signals into long-lasting protein stabilization and enhances the activity of key oncoproteins. A central enzyme in this pathway is the ubiquitin ligase RNF4. An intimate link connects protein stabilization with tumorigenesis in experimental models as well as in the clinic, suggesting that pharmacological inhibition of protein stabilization has potential for personalized medicine in cancer. In this review, we highlight old observations and recent advances in our knowledge regarding protein stabilization.

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Systematic characterization of mutations altering protein degradation in human cancers

Cited by 51 publications

References 128 publications

Antibody toolkit reveals N-terminally ubiquitinated substrates of UBE2W

Antibody toolkit reveals N-terminally ubiquitinated substrates of UBE2W

Inhibiting tumor cell-intrinsic UBA6 by inosine augments tumor immunogenicity

From the Evasion of Degradation to Ubiquitin-Dependent Protein Stabilization

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